Biotech Values

[AlpineBV_Miller]

...an SPA for a trial with an adaptive design is almost like not having an SPA at all. The whole point of an SPA is to preempt criticisms that can cause the FDA to reject an application, and an SPA for an adaptive design doesn’t really accomplish this.

This isn't accurate.

Adaptive designs are not a synonym for "we make it up as we go along" (see CTIC). Adaptive designs are rigorously studied and tested by FDA statisticians before they agree to their use in SPA-governed trials. Such designs get far more attention in the SPa process than "normal" statistical approaches. I'd argue a SPA on an adaptive design is less likely to run into trouble on technical statistical grounds because the FDA spends more time on them up front.

FDA stats people encourage companies to attempt adaptive designs, so this is also not a situation where companies go hat-in-hand to try and "convince" the FDA to do something. Most companies refuse because they find it hard to explain the designs to investors. Most management teams can't get their heads around adaptive clinical trial designs and there are only a handful of competent biostatisticians around who can both create the design and explain it in terms management teams (and therefore investors) can understand.

Adaptive designs are designed to only enroll as many patients as necessary to acheive a pre-determined statistical significance corresponding to a clinical benefit (hazard ratio) seen as suitable by clinicians. To approve an adaptive trial design, therefore, the FDA has to agree with how the design controls alpha spend and pre-determine a demonstrated benefit is clinically relevant. Whether adaptive designs are beneficial to the company is largley a function of how the particular design handles alpha spend. While most designers of these trials will tell you there really is no alpha spend, in my experience that is never completely accurate. Whether the threshold HR goes down the more looks you get or the implied p-value goes down, there is some sort of penalty for multiple looks.

In general, however, the adaptive designs allow more looks at a smaller alpha penalty than a traditional design with multiple interim looks. Provided there are controls in place satisfying the FDA the implied interims that are part of every adpative design cannot reasonably result in practice changes or trial conduct changes, they are willing to approve the adaptive design.

The chief worry on the ONCY trial is not the adaptive design. It is the fact they entered a combination Phase III with zero randomized experience with the combination in this disease and very few patients at all treated with this combination in this disease stage.

I would never invest in a company with an adaptive design not blessed by a SPA because there are simply too many assumptions in an adaptive design the FDA could pick apart after the fact. You want all those assumptions agreed upon up front. However, an adaptive design under a SPA gets no special favors -- surprise side effects and/or poor trial conduct are still penalized.

But it's inaccurate to suggest a SPA on an adaptive design is less meaningful than a SPA on a traditional design.